Immunopathogenic events that occur during the course of HIV infection may be mediated directly by interactions between virions and target cells, as well as indirectly by interactions between virion components (i.e., HIV envelope glycoproteins) and cells. We have established systems that allow us to investigate HIV-1 envelope mediated signal transduction of CD4+ lymphocytes and macrophages in vitro. In order to characterize the response of lymphocytes and macrophage to HIV envelopes we have expressed and purified recombinant forms of macrophage tropic and T-cell tropic HIV-1 and SIV envelope proteins. We have demonstrated that HIV envelope proteins interact directly with the HIV-1 coreceptor CCR5 in addition to the CD4 receptor. We have further demonstrated that this interaction results in signal transduction as measured by calcium mobilization. These responses occur in both CD4+ T-lymphocytes and macrophages. Furthermore these responses are dependent upon the coreceptor specificity of the envelope employed. Only macrophage tropic envelopes are able to induce signals through the CCR5 receptorWe have further addressed the potential pathogenic role of HIV envelope proteins by characterizing intracellular signalling events associated with envelope-receptor interaction. To this end we have identified phosphorylation events associated with envelope ligation of CD4 and CCR5. A variety of proteins were phosphorylated in CD4+ T cells exposed to HIV envelope protein; these included pyk2, focal adhesion kinase (FAK), ZAP70, paxillin, lck, and CCR5. The HIV envelope-induced phosphorylation of these proteins was CD4-dependent; however, the phosphorylation of ZAP70 and CCR5 was mediated at least in part by binding of HIV envelope to CCR5 on the cell surface. Treatment of CD4+ T cells with HIV envelope resulted in an activation complex composed of FAK and CCR5, and redistribution of FAK to focal adhesion complexes. Finally, we have identified an interaction between HIV and SIV envelope proteins and the CD40 receptor. We have demonstrated that envelope proteins bind to the CD40 receptor on macrophages and B-cells. This interaction is partially dependent upon interactions with the CD4 receptor. As a consequence of envelope-CD40 ligation we have shown that macrophages secrete Beta-chemokines and pro-inflammatory cytokines. Moreover, inhibition of this interaction suppresses the replication of HIV in macrophage cultures.